Stroke is a leading cause of death and permanent disability, with an estimated impact on public health of $73.7 billion per year in the United States. Ischemic stroke accounts for over 85% of stroke cases. Therapeutic options for ischemic stroke are limited. Early treatment with recombinant tissue-plasminogen activator (tPA) only benefits a fraction of patients. In addition, this treatment does not target immuno-inflammatory events during stroke. Ischemia-reperfusion damage is associated with dysregulation of multiple neuroinflammatory signaling pathways that causes irreversible damage to neuronal circuits resulting in the pathologies that affect stroke survivors. Our multi-PI team with extensive, complementary, and unique expertise and access to multiple research tools will use a rat model to investigate the efficacy of a novel approach to pharmacologically resolve neuroinflammatory disruptions triggered by experimental ischemic stroke and thus preserve neuronal network integrity and promote neurologic recovery. Our central hypothesis is that blocking pro- inflammatory platelet activating factor receptor (PAFR) together with administration of docosanoids will lead to sustained neurological recovery and protect neuronal circuits in the primary motor cortex after ischemic stroke. Compelling preliminary data support this hypothesis. We have identified a low molecular weight PAFR antagonist, LAU-0901, which will be administered together with the aspirin-triggered (AT) isomer, AT-NPD1 (aspirin-triggered neuroprotectin D1), our lead docosanoid, in the studies proposed for this application. We predict that our new experimental combination therapy that targets mechanisms of motor circuit damage by blocking pro-inflammatory PAF signaling will reduce damage and enhance survival by ensuring the availability of pro-resolving and neuroprotective lipid mediators following middle cerebral artery occlusion (MCAo). We propose two specific aims: 1) To test the hypothesis that combined blocking of pro- inflammatory PAF plus treatment with docosanoids after MCAo will lead to sustained neurological recovery, and 2) Test the prediction that pro-homeostatic lipid mediator pathways are restored by combination treatment for experimental ischemic stroke. The scientific premise of the proposed research is to identify key network processes in adaptive brain plasticity, which may help to predict functional outcome and may also lead to development of therapeutic interventions to support and promote recovery after stroke. This innovative therapeutic approach may also be applicable to the treatment of other neurological diseases with an inflammatory component such as Alzheimer's disease, Parkinson's disease and others.